Intravenous administration of tramadol

ABSTRACT

A method of treating pain, e.g., acute post-operative pain, by intravenously administering to a human patient(s) a dose of tramadol of about 45 mg to about 80 mg, based on tramadol hydrochloride, together with an intravenous dose of acetaminophen in an amount from about 500 mg to about 1000 mg, about every 6 hours.

BACKGROUND OF THE INVENTION

Tramadol is a centrally acting synthetic analgesic with a dual mechanismof action attributed to the racemic form of the drug, comprised ofμ-opioid activity (binding to μ-opioid receptors and monoamine(serotonin and noradrenalin) reuptake inhibition. Tramadol is an analogof the phenanthrene group of opium alkaloids, which includes morphineand codeine, and is structurally related to these opioids (Grond S andSlabotzi A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43:879-923). Like codeine, there is a substitution of the methyl groupon the phenol ring that imparts a relatively weak affinity for opioidreceptors. (+)-Tramadol is a more potent inhibitor of serotonin uptake,while (−)-tramadol is a more potent inhibitor of norepinephrine uptake.The opioid-like activity of tramadol derives from low affinity bindingof the parent compound to μ-opioid receptors and higher affinity bindingof its main metabolite. Tramadol affinity to μ opioid receptors is about10 times weaker than codeine 60 times weaker than dextropropoxyphene and6,000 times weaker than morphine. The active metaboliteO-desmethyltramadol (M1) possesses a higher affinity to the μ opioidreceptor than tramadol and displays analgesic activity (Leppert W,2009).

Tramadol was originally developed by the German pharmaceutical companyGrunenthal GmbH in the late 1970s and is marketed globally under thetrade names TRAMAL® and others outside of the United States. Theapproved doses of tramadol are 50 mg or 100 mg administered as a slowinjection every 4-6 hours (Tramadol Core Product Label, 2008). In theU.S., tramadol is approved by the Food and Drug Administration (FDA) andmarketed as an oral capsule/tablet for moderate to moderately severepain in adults. Tramadol was first approved in the US in April 1995under the trade name, ULTRAM® (Ortho-McNeil-Janssen Pharmaceuticals,Inc). Tramadol is also an active agent in an extended release product,Ultram® ER, and a combination product with acetaminophen, ULTRACET®. Inthe US, tramadol is only available as immediate release tablets orextended release tablets. Other tramadol formulations approved inseveral countries include tablets, capsules, effervescent powders, andsuppositories (Grond and Sablotzki, 2004; Rosenberg, 2009). The approvedintravenous regimen in India is an initial injection of 50 mg infusionover 2-3 min, followed by 50 mg every 10-20 minutes if necessary up to250 mg for the first hour. Maintenance doses are 50-100 mg every 4-6hours with a maximum dose of 600 mg daily (Tramadol, CIMS Data_India).

Postoperative pain management with tramadol has effectively utilized avariety of delivery methods, including bolus injection (IV or IM),continuous infusions and patient controlled analgesia (PCA) pumps, andvarious combinations of these methods (Scott and Perry, 2000; Grond andSablotzki, 2004). The potency ratio of IV tramadol to IV morphine isapproximately 1:10, while the ratio for IV fentanyl is 1:979 (Grond andSablotzki, 2004).

The “on-demand” analgesic efficacy of tramadol was compared to morphinein the 24-hour post-operative period for 523 patients undergoingabdominal surgery (Vickers M D, Paravicini D. Comparison of tramadolwith morphine for post-operative pain following abdominal surgery. Eur JAnesthesiol. 1995; 12: 265-71). Patients who reported post-operativepain received an initial dose (either tramadol 100 mg or morphine 5 mgi.v.) and, if necessary, repeat i.v. or i.m. doses of tramadol 50 mg ormorphine 5 mg on demand over the first 90 minutes. Further doses up to atotal of 400 mg tramadol or 40 mg morphine could then be given after 90minutes up to 24 hours after the first dose of study medication. Theprimary efficacy parameter was the responder rate (no or slight pain)within the first 90 minutes of treatment. Responder rates were 72.6% fortramadol and 81.2% for morphine, which were statistically equivalent andwithin the predefined range of ±10%. Mean cumulative doses were 188.2 mgfor the first 90 minutes and 157.1 mg for the subsequent 22.5 hours inthe tramadol group and 13.9 mg and 18.4 mg, respectively in the morphinegroup. The main adverse events were gastrointestinal in both groups,with mild nausea, dry mouth, vomiting, dyspepsia and hiccups reportedmost frequently.

The analgesic effect of continuous infusion of tramadol was compared torepeated bolus administration in 135 patients undergoing abdominalsurgery (Rud U, Fischer M V, Mewes R, Paravcini D., “PostoperativeAnalgesie mit Tramadol Kontinuierliche Infusion versus repetitive”(Postoperative analgesia with tramadol. Continuous infusion versusrepetitive bolus administration), Bolusgabe Anaesthesist. 1994;43:316-321. (German)). Patients were randomized at the time of the firstrequest for pain treatment. All patients received a loading dose oftramadol 100 mg i.v. Subsequent treatment was administered in adouble-blind manner; patients in the infusion group were given acontinuous infusion of tramadol 12 mg/h for 24 hours, whereas patientsin the bolus group received placebo infusion. In both groups, additionalbolus doses of tramadol 50 mg i.v. were given as required. Pain reliefwas monitored by means of a visual analog scale (VAS) up to 6 hoursafter surgery. The number of additional boluses and the amount oftramadol administered at 6 hours and 24 hours was also used to assessanalgesic efficacy. More patients in the infusion group assessed theirpain relief as excellent or good compared to the bolus group (76.5% vs65.6%). Only a few patients complained of insufficient analgesia, withmore patients in the bolus group reporting inadequate pain relief thanin the infusion group (7.5% vs 4.4%). A higher percentage of patients inthe bolus group required two or more boluses compared to the infusiongroup (59.7% vs 30.8%). After 6 hours, the average tramadol consumptionwas 223.5±53.7 mg in the infusion group and 176.6±63.1 mg in the bolusgroup (p≤0.05). After 24 hours, tramadol consumption was 449.5±66.0 mgand 201.6±83.9 mg (p≤0.001), respectively. Adverse events were reportedby 25% of patients in both groups, with no significant differences andno patient terminated the trial for an adverse event. There were nosignificant effects on blood pressure or heart rate. The authorsconcluded that continuous infusion was more effective in the first 6hours after surgery. However, excess consumption by the infusion groupwas statistically greater than the bolus group at both 6 hours and 24hours post-surgery.

Intermittent bolus and continuous infusion of tramadol were evaluated ina postoperative study of 35 patients undergoing major abdominalgynecologic surgery (Chrubasik J, Buzina M, Schulte-Monting J,Atanassoff P, Alon E. Intravenous tramadol for post-operativepain-comparison of intermittent dose regimens with and withoutmaintenance infusion. Eur J Anaesthesiol. 1992; 9:23-28). The study wasrandomized and double-blind and used tramadol infusion 15 mg/h orsaline. Additional boluses of tramadol 100 mg were given as requested.The patients in the infusion group required 60% less tramadol on demand(p<0.01) and had better pain relief (p<0.05), as assessed by VAS, thanthe group that received the saline infusion. Total tramadol consumption,however, was about 30% higher in the infusion group (p<0.05) and wasassociated with and increased incidence of minor adverse events.Tramadol was ineffective as pain relief within 2 hours of the beginningof treatment in 6% of the infusion group and 20% of the bolus group.Thus, continuous infusion was preferred to “on-demand” bolus treatment.

A meta-analysis of nine randomized, controlled trials indicated thattramadol was as effective as other opioids, including morphine, forcontrol of postoperative pain (Scott and Perry, 2000). Pain in thesepatients was described as moderate to severe, with initial postoperativepain reported as >60 on a 100-point visual analog scale or as moderateor severe on a 4- or 5-point verbal response scale. The first dose ofanalgesia was administered when patients reported moderate to severepain in the postoperative setting. Studies that did not adequatelyrecord baseline pain severity or response to analgesia, were notrandomized or controlled or contained less than 45 patients wereexcluded from the meta-analysis. Tramadol, administered in a dosetitrated to pain response and via either IV (intravenous) or IM(intramuscular) intermittent injection, reduced pain intensity by 46.8%to 57.6% after 4 to 6 hours compared to 69.8% for morphine and 25.6% to51.3% for pentazocine. Efficacy of tramadol was maintained for theduration of the studies, which were ≤72 hours, and was comparable tomorphine or alfentanil. However, the onset of action of tramadol wasslower than morphine, as assessed by measurements approximately 3 hoursafter the first dose. There were no significant differences in thepercentage of patients treated with tramadol or morphine and who alsorequired rescue medication. The patient global response and physicianglobal response were similar for tramadol and for other opioids.

Tramadol injection (IV/IM/SC) is approved and used for the management ofmoderate to severe acute postoperative pain in several regions,including Europe, India and Australia/New Zealand (however, this dosageform is not available in the USA). Tramadol ampoules or vials for IV, IMand SC administration and preservative-free solutions for injection bythe various spinal routes (epidural, intrathecal, caudal, etc.) areavailable forms in these regions. Tramadol formulations approved inseveral countries include, tablets, capsules, effervescent powders, andsuppositories (Grond and Sablotzki, 2004; Rosenberg, 2009).

There is extensive data demonstrating that tramadol use is notassociated with the classical opioid side effects seen with more potentopioids. There are numerous reports of the safety and efficacy oftramadol (Lee et al., 1993; Scott and Perry, 2000; Grond and Sablotzki,2004). The most common adverse events of tramadol administration arenausea, dizziness, headache, somnolence, sweating, fatigue,constipation, dry mouth and vomiting. However, tramadol use,particularly with high doses, has been associated with seizures, and therisk of seizures is increased in the presence of drugs that reduceseizure threshold, head trauma or prior history of seizures.

Patients undergoing surgery, for example, total knee arthroplasty (TKA)and total hip arthroplasty (THA), typically demonstrate a need forshort-term analgesia, which is critical for earlier mobilization andrehabilitation. In this setting, assuring adequate pain relief withoutproviding extensive medical oversight required for some methods oftreatment (such as neuraxial anesthesia) and prevention of effects suchas opiate-induced respiratory depression and dependency would be highlybeneficial (Sinatra et al., 2002).

The goal of post-surgical pain management is twofold: i) to provide aquick onset of analgesic or pain relief and ii) to reduce or modulatethe quality and intensity of pain that a patient experiences in thepost-surgical period. While current treatments for management ofpost-surgical acute pain are useful, there is a need for improvedmethods for treating post-surgical acute pain.

Prior publications report that analgesic potency may be improved whilereducing undesirable effects by combining an opioid with an NSAID or ananalgesic such as acetylsalicylic acid or acetaminophen, in such a wayas to obtain a synergistic analgesic effect allowing for a reduction inthe total dose of both the NSAID and analgesic. For example, U.S. Pat.No. 4,569,937, issued to Baker et al. on Feb. 11, 1986, describes acombination of oxycodone with ibuprofen in a ratio ofoxycodone/ibuprofen from 1:6 to about 1:400. U.S. Pat. No. 4,690,927,issued to Voss et al. on Sep. 1, 1987, describes a combination of theNSAID diclofenac and codeine in a weight ratio of diclofenac to codeineof about 1:1 to about 3:1. U.S. Pat. No. 5,190,947, issued to Riess etal. on Mar. 2, 1993, describes a diclofenac-codeine salt([2-[2,6-dichlorophenyl)-amino]-phenyl]-acetic acid). U.S. Pat. No.4,844,907, issued to Elger et al. on Jul. 4, 1989, describes amultiphase tablet combining a narcotic analgesic phase and an NSAIDphase in separate layers. U.S. Pat. No. 4,587,252, issued to Arnold etal. on May 6, 1986, describes a process for treating pain using acombination of hydrocodone and ibuprofen.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method of treatingpain in human patients.

It is a further object of the present invention to provide a method oftreating pain in human patients who are unable to take oral medications,such as in a post-operative condition.

It is a further object of the present invention to provide a method oftreating pain in human patients that takes advantage of the faster onsetof intravenous administration of tramadol while providing additionalbenefits not available via current methodologies of tramadol intravenousadministration.

It is another object of the present invention to provide a method ofproviding a safe and effective alternative injectable analgesic for usein the acute postoperative setting.

It is another object of the present invention to provide a method fortreating pain in, e.g., the acute postoperative setting which is or maybe opioid-sparing.

It is another object of the present invention to provide a method fortreating pain with intravenous tramadol in human patients in a mannerthat may or does reduce side-effects (such as, e.g., nausea, vomiting orseizure).

It is a further object of the present invention to provide a method oftreating pain with a drug and dosing regimen that provides a positivebenefit-risk profile, and which addresses an unmet medical need for themanagement of acute postoperative pain.

In accordance with the above objects and others, the present inventionis directed in part to the co-administration of intravenous tramadol andintravenous acetaminophen to a human patient(s) to treat acute pain. Incertain embodiments, the co-administration occurs either prior to,during, or after surgery.

In accordance with the above objects and others, the present inventionis directed in part to a method of administering tramadol for treatingpain via an intravenous dosing regimen comprising intravenouslyadministering a first dose of tramadol to a human patient in an amountfrom about 45 mg to about 80 mg; and concurrently administering anintravenous dose of acetaminophen in an amount from about 500 mg toabout 1,000 mg; and thereafter intravenously administering the doses oftramadol and acetaminophen about every 5 to about every 7 hours,preferably about every 6 hours until the patient no longer requirestreatment with intravenous tramadol. The intravenous dosing regimenprovides a Cmax of tramadol which is similar to the Cmax of an oral doseof 100 mg tramadol HCl given every 6 hours at steady-state. In certainpreferred embodiments, each dose of tramadol is about 60 mg. Theintravenous dosing regimen preferably provides a Cmax of tramadol whichis similar to the Cmax of an oral dose of 100 mg tramadol HCl givenevery 6 hours at steady-state. In certain preferred embodiments, eachdose of tramadol is about 60 mg tramadol hydrochloride. In certainfurther preferred embodiments, each dose of acetaminophen is about 650to about 750 mg.

In certain preferred embodiments, the intravenous dosing regimen of theinvention provide a Cmax of tramadol at steady-state that is from about80% to about 125% of the Cmax provided at steady-state by a 100 mg oraldose of tramadol HCl given every 6 hours, e.g., the intravenous dosingregimen provides a Cmax of tramadol at steady-state from about 80% toabout 125% of about 736 ng/mL. The method may further comprisecontinuing to administer additional doses of tramadol and acetaminophento the human patient for at least about 42 hours after the firstadministered dose of tramadol.

In certain preferred embodiments, the method further comprises dilutingthe dose of tramadol and acetaminophen in from about 50 ml to about 500ml of a pharmaceutically acceptable fluid for injection, andstandardizing the administration of the injection of the dose oftramadol and acetaminophen via the use of a pump. The dose may beprovided in the form of a sterile solution at a concentration of about60 mg tramadol hydrochloride and from about 500 mg to about 1,000,preferably from about acetaminophen contained in one or more ampoules orvials. The ampoules may contain the dose of tramadol togetheracetaminophen with a buffering agent in solution for injection, or theampoules/vials may separately contain the dose of tramadol in oneampoule and the dose of acetaminophen in another ampoule. In certainembodiments, the method further comprises diluting the dose of tramadoland acetaminophen into an IV bag for administration to the humanpatient.

The first dose of tramadol/acetaminophen may be administered to thehuman patient intra-operatively at wound closure, or from first demandof analgesia postoperatively, and administering further doses ofintravenous tramadol/acetaminophen for at least two days post-surgery.In certain embodiments, the human patient is suffering from acutepost-operative pain.

The method may further comprise switching the human patient after atleast three intravenous doses of tramadol/acetaminophen, to oral dosesof the same amount of tramadol and acetaminophen previously administeredintravenously, such that the Cmax of tramadol at the time the humanpatient is switched to oral doses is similar to the Cmax provided atsteady-state by a dosing regimen of 100 mg tramadol HCl administeredorally every 6 hours.

The method may further comprise administering an opioid analgesic whichis not tramadol to the human patient to treat breakthrough pain.

In certain preferred embodiments, the invention is directed to a methodof administering tramadol for treating pain via an intravenous dosingregimen, comprising intravenously administering a first dose of tramadolto a human patient in an amount of about 45 mg to about 80 mg (e.g.,about 60 mg); and concurrently administering an intravenous dose ofacetaminophen in an amount of about 500 to 1,000 mg (e.g., about 650mg); and thereafter intravenously administering the doses of tramadoland acetaminophen about every 5 to about 7 hours (e.g., preferably aboutevery 6 hours) until the patient no longer requires treatment withintravenous tramadol, wherein the tramadol is tramadol base or apharmaceutically acceptable salt of tramadol, such that the intravenousdosing regimen provides a Cmax of tramadol which is similar to the Cmaxof an oral dose of 100 mg tramadol HCl given every 6 hours atsteady-state. The intravenous dosing regimen of the invention preferablyprovides a Cmax of tramadol at steady-state that is from about 80% toabout 125% of the Cmax provided at steady-state by a 100 mg oral dose oftramadol HCl given every 6 hours, e.g., the intravenous dosing regimenprovides a Cmax of tramadol at steady-state from about 80% to about 125%of about 736 ng/mL.

In certain preferred embodiments, the intravenous dosing regimens of theinvention provide a Cmax of the M1 metabolite of tramadol atsteady-state that is from about 20% to about 125% (in certainembodiments from about 60% to about 75%), or from about 80% to about125% of the Cmax of the M1 metabolite of tramadol at steady-state whenthe tramadol is administered as oral 100 mg tramadol HCl every 6 hours.

In certain embodiments of the intravenous dosing regimens of theinvention, the intravenous dosing regimen provides a Cmax of tramadol atsteady-state from about 80% to about 125% of about 736 ng/mL.

In preferred embodiments of the intravenous dosing regimens of theinvention, each dose of tramadol and acetaminophen is administeredintravenously over a time period from about 10 minutes to about 20minutes. In certain preferred embodiments, each dose of the tramadol andacetaminophen is administered over a time interval of 15 (±2) minutes.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering a firstintravenous dose of tramadol and acetaminophen to the patientintra-operatively at wound closure, or from first demand of analgesiapost-operatively, and administering said further doses of intravenoustramadol for at least two days post-surgery.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering one or moredoses of an intravenous opioid analgesic as rescue medicine to thepatient to treat breakthrough pain.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering the first doseof tramadol and acetaminophen on first demand of analgesiapost-operatively, further comprising administering a therapeuticallyeffective dose intravenous opioid analgesic to the patient at the end ofthe surgery.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering the first doseof tramadol and acetaminophen to the patient intra-operatively at woundclosure, further comprising administering a bolus of a therapeuticallyeffective dose of intravenous opioid analgesic to the patient if thepatient requests analgesia before the second dose of intravenoustramadol/acetaminophen.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering a rescueopioid analgesic using Patient Controlled Analgesia (PCA).

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the treatment of pain in the patient is conventionalopioid-sparing over the first, e.g., 24, 30, 36, 42 or 48 hourspost-surgery.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises diluting tramadol in avolume of normal saline to provide a unit dose from about 45 mg to about80 mg tramadol and from about 500 to about 1,000 mg acetaminophen in avolume of normal saline; administering the dose intravenously over atime period, e.g., from about 15 (±2) minutes. In certain preferredembodiments of the intravenous dosing regimens of the invention, themethod further comprises diluting tramadol in a volume of normal salineto provide a unit dose of about 60 mg tramadol and from about 650 toabout 750 mg acetaminophen in a volume of normal saline; administeringthe dose intravenously over a time period, e.g., from about 15 (±2)minutes.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the dose prior to dilution is contained in one or moreampoules.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the ampoules contain tramadol hydrochloride,acetaminophen, and a buffering agent in water for injection.

In certain embodiments of the intravenous dosing regimens of theinvention, the human patient(s) is suffering from acute post-operativepain.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method provides a reduction in at least oneside-effect associated with tramadol therapy (e.g., as compared to priorart intravenous dosing regimens), wherein the side-effect is nausea,vomiting, or seizure.

In certain preferred embodiments of the intravenous dosing regimens ofthe invention, the method further comprises administering atherapeutically effective dose of an intravenous opioid analgesic isadministered to the patient (i) at the end of the surgery, (ii) if thepatient requests analgesia before the second dose of tramadol, or (iii)both (i) and (ii).

In certain preferred embodiments, the present invention is directed inpart to a method of treating pain, comprising administering to a humanpatient(s) a therapeutically effective dose of tramadol andacetaminophen intravenously over a time period from about 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20 21, 22, 23, 24, 25, 26, 27, 28, 29 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 or 45 minutes.

Further aspects of the invention are directed to diluting the dose oftramadol and acetaminophen in from about 50 ml to about 500 ml (andpreferably from about 50 ml to about 100 ml) of a pharmaceuticallyacceptable fluid for injection such as normal saline, e.g., in a bag orvial, and standardizing the administration of the injection of the doseof tramadol and acetaminophen via the use of a pump. In anotherembodiment, the dose is provided in the form of a sterile solutioncomposed of about 60 mg tramadol hydrochloride and about 500 to 1,000mg.

In certain further preferred embodiments, the dose of tramadol prior todilution is contained in one or more ampoules. In certain preferredembodiments, the ampoules may contain the dose of tramadol (e.g.,tramadol hydrochloride) together acetaminophen, alone or with abuffering agent (e.g., sodium acetate) in water for injection (e.g.,about 1 ml to about 5 ml).

In certain further preferred embodiments, the method further comprisesdiluting the dose of tramadol and acetaminophen into an IV bag orampoule/vial for administration to the patient.

In certain preferred embodiments of the present invention, the methodfurther comprises administering a first dose of tramadol/acetaminophento the patient intra-operatively at wound closure, or from first demandof analgesia postoperatively, and administering said further doses ofintravenous tramadol/acetaminophen for at least two days post-surgery.

In certain preferred embodiments of the present invention, the methodfurther comprises the concomitant administration of one or more opioidanalgesics, preferably via the injectable (e.g., intravenous) route asrescue medicine to the patient to treat breakthrough pain that thepatient experiences, e.g., for the time period of at least about 48hours post-surgery. Several options are available for postoperative painmanagement (Singelyn et al., 1998; Sinatra et al., 2002; both of whichare hereby incorporated by reference). Options include intermittent“on-demand” analgesia, continuous epidural analgesia with opioids and/orlocal anesthetics is effective, or to provide a combination of nerveblocks with long-acting local anesthetics and/or opioids initiatedintra-operatively and continued into the immediate postoperative period.For example, most Total knee Arthroplasty (TKA) or Total HipArthroplasty (THA) procedures are currently performed with regional (orneuraxial) or other nerve blocks and without general anesthesia. Incertain preferred embodiments of the invention, the method furthercomprises administering a rescue opioid analgesic using PatientControlled Analgesia (PCA). In certain preferred embodiments, theintravenous administration of opioid analgesic also or alternativelycomprises opioid analgesic (e.g., morphine) intravenously to the patientat an effective dose (e.g., morphine in an amount of about 0.05 mg/kg)as a bolus at the end of surgery or upon first demand of analgesiapostoperatively, to provide effective analgesia to the patient(s).

In certain preferred embodiments of the invention, the first dose oftramadol is administered on first demand of analgesia postoperatively.Thereafter, the method may further comprise administering atherapeutically (analgesically) effective dose intravenous opioidanalgesic to the patient at the end of the surgery, to provide effectiveanalgesia to the patient(s).

In certain preferred embodiments of the invention, the first dose oftramadol is administered to the patient intra-operatively at woundclosure. In such embodiments, the method may further compriseadministering a bolus of a therapeutically (analgesically) effectivedose of intravenous opioid analgesic to the patient if the patientrequests analgesia before the second dose of tramadol, to provideeffective analgesia to the patient(s).

In preferred embodiments where the tramadol is administered for thetreatment of post-operative pain, the treatment of pain in the patientis opioid-sparing over the first 48 hours post-surgery.

In other preferred embodiments, the human patient(s) suffering from painis unable to ingest an oral dosage form (e.g., of tramadol or anotheropioid analgesic and/or an NSAID) because the patient is suffering fromcancer pain.

In accordance with the above, the final drug product (containing theintravenous dose of tramadol) may be presented as, e.g., as unit-doseampoules, unit-dose vials, multi-dose ampoules, multi-dose vials, anddrug in pre-mixed bags.

In certain preferred embodiments, the M1 metabolite of tramadol(0-desmethyltramadol) contributes to analgesic effect provided by thepresent invention (dosing regimen), without being toxic (e.g., withoutsignificant side effects) to humans at the administered dose ofintravenous tramadol.

In certain embodiments, the method may provide a faster onset of painrelief than oral doses of 100 mg tramadol HCl given every 6 hours.

The invention is further directed in part to the above methods, whereinthe safety and tolerability of tramadol for treating pain in humanpatients is improved.

In certain preferred embodiments, the pharmacokinetic profile (e.g.,Cmax) achieved by this 45-80 mg, preferably about 60 mg IV tramadoldosing regimen at a time where the patient might be switched to oralmeds (e.g., after the 44-48 hour dosing interval) is similar to thepharmacokinetic profile (e.g., Cmax) provided at steady-state by adosing regimen of 100 mg tramadol HCl administered orally every 6 hours.This allows the patient to be stepped down from the intravenous tramadoldosing regimen to an oral dosing regimen. In turn, this allows thepatient to be discharged from hospital care with less concern aboutdeleterious effects which might occur from a switch from intravenous tooral analgesic medicine (e.g., the switch to an oral version of the drugproviding a much different Cmax).

The term “about 60 mg” should be construed with the goal of the presentinvention in mind—the dose of the dose (“about”) may be adjusted to alimited degree, e.g., as long as the goal of a mean Cmax which issimilar to the mean steady-state Cmax that is obtained via theadministration of an oral dosing regimen of 100 mg tramadol administeredto human patients every 6 hours (if the dosing regimen is continued for48 hours). Generally speaking, it should be recognized that the adose(s) of the drug may be modified (e.g., intravenous tramadol may bemodified, e.g., to a dose from about 45 mg to about 80 mg andintravenous acetaminophen may be modified to a dose from about 500 mg toabout 1000 mg, or from about 650 mg to about 750 mg) and a dosinginterval for the second dose and onward of intravenoustramadol/acetaminophen may be modified, e.g., as long as the goal of amean Cmax of tramadol is obtained which is similar to the meansteady-state Cmax is obtained via the administration of an oral dosingregimen of 100 mg tramadol administered to human patients every 6 hours(if the dosing regimen is continued for 48 hours) in order to providetreatment of pain (e.g., acute pain) in the human patient(s).

In additional embodiments, the invention is directed to a method ofreducing surgical pain in human patients, comprising administering theintravenous dosing regimen of tramadol and acetaminophen as describedherein, such that the patient experiences relief from pain associatedwith the surgery. In preferred embodiments, the method further comprisesintravenously co-administering a 60 mg dose of intravenous tramadol andabout a 650 to about 750 mg dose of acetaminophen about every six hourspost-operatively to the patient. Preferably, the intravenoustramadol/acetaminophen therapy is continued until the patient no longeris suffering from post-operative pain.

Additional embodiments of the present invention are directed to a kit,comprising a vial containing an intravenous dose of tramadol or apharmaceutically acceptable salt thereof in an amount from about 45 mgto about 80 mg (based on the hydrochloride salt); and a vial containingan intravenous dose of acetaminophen in an amount from about 500 mg toabout 1,000 mg. In certain embodiments, the kit contains additionaldoses of tramadol and acetaminophen. In certain preferred embodiments,the kit contains sufficient doses of tramadol and acetaminophen to beadministered about every 5 to about every 7 hours (e.g., about every 6hours) until the patient no longer requires treatment with intravenoustramadol, e.g., up to about 48 hours after initiation of dosing (e.g.,about 8 doses of each drug). In certain embodiments, the doses oftramadol HCl and acetaminophen are contained within the same vial, andthe kit contains separate vials for each dosing interval, e.g., untilthe patient no longer requires treatment with intravenous tramadol,e.g., up to about 48 hours after initiation of dosing (e.g., about 8doses). In other embodiments, the doses of tramadol HCl andacetaminophen are contained within separate vials, and the kit containsvials for each dosing interval, e.g., until the patient no longerrequires treatment with intravenous tramadol, e.g., up to about 48 hoursafter initiation of dosing (e.g., about 8 doses). The intravenous dosingregimen contained in the kit preferably provides a Cmax of tramadolwhich is similar to the Cmax of an oral dose of 100 mg tramadol HClgiven every 6 hours at steady-state. In certain preferred embodiments,each dose of tramadol is about 60 mg. In certain preferred embodiments,each dose of acetaminophen is from about 650 mg to about 750 mg.

The methods of the present invention are described in further detail inthe following sections. However, it should be understood that forpurposes of the present invention, the following terms have thefollowing meanings:

The term “acute pain” as used herein means pain that has a sudden onsetand commonly declines over a short time (days, hours, minutes) andfollows injury to the body and which generally disappears when thebodily injury heals.

The term “effective analgesia” is defined for purposes of the presentinvention as a satisfactory reduction in or elimination of pain, alongwith the process of a tolerable level of side effects, as determined bythe human patient.

The term “effective pain management” means for purposes of the presentinvention as the objective evaluation of a human patient's response(pain expressed versus side effects) to analgesic treatment by aphysician as well as subjective evaluation of therapeutic treatment bythe patient undergoing such treatment. The skilled artisan willunderstand that effective analgesia will vary according to many factors,including individual patient variations.

The term “breakthrough pain” means pain which the patient experiencesdespite the fact that the patient is being administered generallyeffective amounts of, e.g., an opioid analgesic such as buprenorphine.

The term “rescue” refers to a dose of an analgesic which is administeredto a patient experiencing breakthrough pain.

An “effective amount” is an amount sufficient to effect beneficial ordesired clinical results including alleviation or reduction in pain. Insome embodiments, the “effective amount” may reduce the pain of ongoingpain and/or breakthrough pain (including ambulatory pain andtouch-evoked pain).

The term “parenterally” as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques.

The term “patient” as used herein refers to a warm blooded animal suchas a mammal which is the subject of trauma, e.g., surgical trauma. It isunderstood that at least humans, dogs, cats, and mice are within thescope of the meaning of the term.

As used herein, the term “treat” or “treatment”, or a derivativethereof, contemplates partial or complete inhibition of acute pain, whena composition of the present invention is administered following theonset of acute pain.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

As used herein a “dosage regimen” refers to the protocol used toadminister an intravenous pharmaceutical formulation comprisingibuprofen to a patient. In some embodiments the dosage regimen comprisesa dose amount and dosing interval.

DETAILED DESCRIPTION

The chemical name for tramadol is(±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanolhydrochloride [or(1R,2R)-rel-2-[(dimethyl-amino)methyl]-1-(3-methoxyphenyl) cyclohexanolhydrochloride, (1RS, 2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride, (±)-(RR,SS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanolhydrochloride]. Unless otherwise specified, the term tramadol refers tothe racemic mixture of the (±)cis isomers.

Tramadol is a centrally-acting synthetic analgesic of theaminocyclohexanol group with opioid-like effects. Tramadol isextensively metabolized following administration resulting in a numberof enantiomeric metabolites which display different opioid-receptorbinding properties, and monoaminergic reuptake inhibition (Grond andSablotzki, 2004). Both enantiomers of tramadol and (+)-M1 areresponsible for the analgesic effect. The primary metabolite [(+)-M1 or(+)-O-desmethyltramadol] of tramadol confers significant μ-opioidactivity; (+)-tramadol confers weak μ-opioid activity and significantserotonin reuptake inhibition; and (−)-tramadol is responsible for theinhibition of noradrenaline re-uptake (Gillen et al., 2000; Raffa,2008). Nonclinical studies have shown that antinociception induced bytramadol is only partially antagonized by the opiate antagonist,naloxone, indicating that non-opioid mechanisms are also involved in itspharmacodynamic action (Collart et al., 1992).

Tramadol has efficacy in management of acute postoperative painequivalent to morphine and other opioids administered intravenously,although the onset of action for tramadol is slower. The parenteralroute has the advantage of immediate bioavailability and faster onset ofaction than oral, and is available to postoperative patients who cannottake oral medications. Current standard-of-care injectable analgesics(opioids and NSAIDs) have significant adverse effects, includingopiate-induced respiratory depression, excessive sedation, hypotension,dependency, increased bleeding risk, renal toxicity and gastrointestinalirritation, which can potentially slow the postoperative rehabilitationprocess and compound the risk inherent in any surgical procedure.

Tramadol is currently commercially available in variouscountries/territories in the following forms: 50 mg/ml or 100 mg/2 ml,solution for injection; 50 mg, capsules, hard; 50 mg, prolonged-releasetablets; 100 mg, prolonged-release tablets; 150 mg, prolonged-releasetablets; 200 mg, prolonged-release tablets; 50 mg, tablets; 100 mg/ml,oral drops, solution; and 100 mg, suppositories. In the U.S., tramadolis approved by the Food and Drug Administration (FDA) and marketed as anoral capsule/tablet for moderate to moderately severe pain in adults,e.g., under the tradename Ultram® (tramadol hydrochloride tablets).

Parenteral tramadol has been used extensively in Europe and other areasof the world for the amelioration of postoperative pain in both adultsand children. The efficacy of tramadol has been thoroughly reviewed (LeeC R, McTavish D, Sorkin E M. Tramadol. A preliminary review of itspharmacodynamic and pharmacokinetic properties, and therapeuticpotential in acute and chronic pain states. Drugs. 1993; 46:313-340;Scott J L, Perry C M. Tramadol. A review of its use in perioperativepain. Drugs. 2000; 60:139-176; Grond S and Slabotzi A. Clinicalpharmacology of tramadol. Clin Pharmacokinet. 2004; 43:879-923).Parenteral tramadol in such territories consists of tramadol 50 mg or100 mg administered as a slow bolus injection (over 2-3 minutes) every4-6 hours.

Acetaminophen is a non-salicylate antipyretic and non-opioid analgesicagent. Its chemical name is N-acetyl-p-aminophenol. Acetaminopheninjection is indicated for the management of mild to moderate pain; themanagement of moderate to severe pain with adjunctive opioid analgesics;and the reduction of fever. Acetaminophen injection is available in theU.S. under the tradename Ofirmev™ from Cadence Pharmaceuticals, Inc. Itis supplied in a 100 mL glass vial containing 1000 mg acetaminophen (10mg/mL) and the vials are approved for single use only. Acetaminopheninjection can be administered, e.g., as a 15 minute infusion or as a 30minute infusion, and may be administered every 4 to 6 hours. The maximumrecommended dose of acetaminophen on a daily basis to adults is 4000 mg.Ofirmev injection is a sterile, clear, colorless, non-pyrogenic,isotonic formulation of acetaminophen for intravenous infusion. It is apH of about 5.5 and an osmolality of about 290 mOsm/kg. Each 100 mLcontains 1000 mg acetaminophen, USP, 3840 mg mannitol, USP, 25 mgcysteine hydrochloride, monohydrate, USP, 10.4 mg dibasic sodiumphosphate, anhydrous, USP. The pH is adjusted with hydrochloric acidand/or sodium chloride. The dosage of Ofirmev for adults and adolescentsweighing 50 kg and over is 1000 mg every 6 hours or 650 mg every 4hours, with a maximum single dose of Ofirmev of 1000 mg and a minimumdosing interval of 4 hours and a maximum daily dose of acetaminophen of4000 mg per day. For adults, adolescents weighing under 50 kg, andchildren from 2 to 12 years of age, the recommended dosage of Ofirmev is15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours, with a maximumsingle dose of Ofirmev of 15 mg/kg, and a maximum daily dose ofacetaminophen of 75 mg/kg per day.

In certain preferred embodiments, the intravenous tramadol andacetaminophen doses are administered intravenously at the same timepost-surgery, at dosing intervals of every 4 to about every 6 hours. Incertain preferred embodiments, the tramadol and acetaminophen doses arecontained within a single unit dose, e.g., inside a vial.

The invention is further directed to a method of treating atpost-surgical patient in need of pain relief comprising administering tothe patient an intravenous pharmaceutical composition comprisingintravenous tramadol together with intravenous acetaminophen. In certainpreferred embodiments of this method, the dose of acetaminophen producesa decreased need for tramadol and/or a additional opioid analgesic,decreased side effects from use of a narcotic analgesic and/or decreasedperception of pain.

The co-administration of intravenous tramadol and acetaminophen used inaccordance with the invention provides a treatment for pain and/or feverusing the intravenous route of administration, and is useful, e.g., forthe treatment of mild to severe pain (and particularly acute pain) inadults and children over 12 years of age. Co-administration ofintravenous tramadol and acetaminophen used in accordance with themethods of the invention provides pain control, e.g., for abdominal andorthopedic surgical procedures; may be opioid sparing when used forpost-operative pain; may provide a reduction in opioid side effects;provides a reduction in adverse events, may provide a reduction in theneed for anti-emetic medications, may allow patients to becomeambulatory faster.

The co-administration of intravenous tramadol and acetaminophen inaccordance with the present invention may provide the followingbenefits, for example: speeds relief of pain to expedite release from ahospital or hospital-like setting; speeds relief to expedite hospitalrelease, as demonstrated by a fast reduction of mild to severe pain inadults and children over 12 years of age; a reduction in pain at restand with movement as measured by visual analog scores (VAS) followingabdominal and orthopedic surgeries; a reduction in opioid side effects(nausea, vomiting, constipation); preferably does not cause bleeding orrenal concerns; and may provide an improvement in time to ambulationwhich may enable facilities to schedule additional procedures in theambulatory setting.

Surgical procedures often result in some form of acute pain. Surgicalpain may include nociceptive, neuropathic or psychological components.Nociceptive pain is a pain experienced as a result of nociception, whichis detection of a stimulus by a pain receptor (nociceptor) andtransmission of the information to the brain along nerves. Nociceptivepain is caused by tissue damage and inflammation in response to trauma.The resulting pain is usually not well localized and is opioidresponsive.

Several options are available for postoperative pain management(Singelyn et al., 1998; Sinatra et al., 2002). Options includeintermittent “on-demand” analgesia, continuous epidural analgesia withopioids and/or local anesthetics is effective, or to provide acombination of nerve blocks with long-acting local anesthetics and/oropioids initiated intra-operatively and continued into the immediatepostoperative period. In the United States (US) and in India, thislatter strategy is frequently employed, and most TKA and THA proceduresare currently performed with regional (or neuraxial) or other nerveblocks and without general anesthesia. Each of these options forpostoperative pain management can be used concomitantly with theintravenous tramadol treatments described herein as recue medicine totreat breakthrough pain.

The present invention is directed in part to tramadol and acetaminophenin a pharmaceutically acceptable sterile solution formulation(s)containing an effective dose of tramadol or a pharmaceuticallyacceptable salt thereof, either in combination with an effective dose ofacetaminophen or in separate intravenous formulations and a method ofadministration of the same for the treatment of pain, e.g.,postoperatively. Tramadol injection and acetaminophen injection inaccordance with the present invention will fulfill an important need byproviding a safe and effective alternative injectable analgesic for usein the acute postoperative setting.

Preferably, the dose of tramadol administered in accordance with thepresent invention is, e.g., from about 45 mg to about 80 mg, and incertain preferred embodiments from about 45 to about 55 mg, or fromabout 70 to about 80 mg, or from about 55 to about 65 mg. In certainpreferred embodiments, each tramadol dose administered is in the amountof, e.g., 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,78, 79 or 80 mg, e.g., provided as tramadol hydrochloride. The tramadolmay be provided, e.g., as 60 mg tramadol hydrochloride/1 ml. Theinjectable tramadol dose is generally intended for in-hospital use,although it can be used in other settings. In certain preferredembodiments, the tramadol is administered intravenously over a timeperiod from about 10 minutes to about 3 hours. In certain preferredembodiments, the therapeutically effective dose of tramadolintravenously over a time period from about 10 minutes to about 20minutes, and most preferably in certain embodiments about 15 (±2)minutes. Thus, in preferred embodiments, the therapeutically effectivedose of tramadol intravenously over a time period from about 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes.

The dose of acetaminophen is preferably administered intravenouslysimultaneously with the dose of tramadol. The dose of acetaminophen maybe from about 500 to about 1000 mg, preferably from about 650 g to about750 mg. In certain preferred embodiments, the dose of acetaminophen is650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715,720, 725, 730, 735, 740, 745, or 750 mg, i.e., any integer from about650 mg to about 750 mg.

Further aspects of the invention are directed to diluting the dose oftramadol and acetaminophen in from about 50 ml to about 100 ml of apharmaceutically acceptable fluid for injection (such as normal saline),and standardizing the administration of the injection of the dose oftramadol via the use of a pump. In preferred embodiments, the pump is aninfusion pump that is commercially available, such as pumps availablefrom Braun and Hospira.

As previously mentioned, the dose of tramadol administered in accordancewith the present invention may be diluted in a suitable pharmaceuticallyacceptable carrier for injection. Examples of such include sterile waterfor injection, normal saline, etc. Intravenous fluids are well known tothose of ordinary skill in the art, and may include other ingredientsbeyond the dose of tramadol and the carrier/solvent for the tramadol,e.g., sterile solutions of simple chemicals such as sugars, amino acidsor electrolytes, which can be easily carried by the circulatory systemand assimilated. Such fluids are typically prepared with water forinjection USP. Fluids used commonly for intravenous (IV) use aredisclosed in Remington, The Science and Practice of Pharmacy [fullcitation previously provided], and include: alcohol, e.g., 5% alcohol(e.g., in dextrose and water (“D/W”) or D/W in normal saline solution(“NSS”), including in 5% dextrose and water (“D5/W”), or D5/W in NSS);synthetic amino acid such as Aminosyn, FreAmine, Travasol, e.g., 3.5 or7; 8.5; 3.5, 5.5 or 8.5% respectively; ammonium chloride e.g., 2.14%;dextran 40, in NSS e.g., 10% or in D5/W e.g., 10%; dextran 70, in NSSe.g., 6% or in D5/W e.g., 6%; dextrose (glucose, D5/W) e.g., 2.5-50%;dextrose and sodium chloride e.g., 5-20% dextrose and 0.22-0.9% NaCl;lactated Ringer's (Hartmann's) e.g., NaCl 0.6%, KCl 0.03%, CaCl₂) 0.02%;lactate 0.3%; mannitol e.g., 5%, optionally in combination with dextrosee.g., 10% or NaCl e.g., 15 or 20%; multiple electrolyte solutions withvarying combinations of electrolytes, dextrose, fructose, invert sugarRinger's e.g., NaCl 0.86%, KCl 0.03%, CaCl₂) 0.033%; sodium bicarbonatee.g., 5%; sodium chloride e.g., 0.45, 0.9, 3, or 5%; sodium lactatee.g., ⅙ M; and sterile water for injection The pH of such IV fluids mayvary, and will typically be from about 3.5 to about 8 as known in theart.

The dose of tramadol or pharmaceutically acceptable salts thereof andacetaminophen can be administered alone or in combination with othermedical treatments, or other therapeutic agents, such as NSAIDs. Whenso-used, other therapeutic agents can be administered before,concurrently (whether in separate dosage forms or in a combined dosageform), or after administration of an active agent of the presentinvention.

Consistent with the known clinical effects of opioids, nonclinicalsafety pharmacology studies have shown that tramadol at high dosesaffects the central nervous system (CNS), producing sedation, impairedmobility, vomiting (dogs), decreased activity, and convulsions(Matthiesen et al., 1998). Also consistent with clinical effects,changes in blood pressure have been observed in cardiovascular studiesin rats at high doses (Raimundo et al., 2006). Tramadol use,particularly with high doses, has been associated with seizures, and therisk of seizures is increased in the presence of drugs that reduceseizure threshold, head trauma or prior history of seizures.

The toxicity of tramadol has been summarized by Matthiesen, et al.(1998). The single-dose toxicity of tramadol was similar in all speciestested, independent of the route of administration. Notable acutefindings included restlessness, unsteady gait, reduced spontaneousactivity, exophthalmus, mydriasis, salivation, vomiting (dog), tremor,convulsions, slight cyanosis and dyspnea. The principle findings inrepeat-dose toxicity studies in rats and dogs were behavioral/clinicalsigns and convulsions at doses of ≥25 mg/kg/day. The kidney and liverwere identified as potential target organs in rats, with mild effects(minimal tubular vacuolization and perivenular hydropic degeneration,respectively) following repeat intraperitoneal dosing at high doses oftramadol.

There was no evidence of genotoxic potential for tramadol in standard invitro and in vivo studies (Matthiesen et al., 1998). Carcinogenicitybioassays in mice and rats showed no evidence of carcinogenic potential.An extensive reproductive and teratology program revealed no safetyconcerns with respect to fertility or teratogenic effects after oraladministration (Matthiesen et al., 1998; Yamamoto et al., 1972).Toxicity to offspring only occurred at doses associated with maternaltoxicity.

Following oral administration, tramadol is rapidly and almost completelyabsorbed. The pharmacokinetics of tramadol were evaluated in healthymale volunteers (n=10) in a crossover design using 100 mg PO or IV doses(Lintz et al., 1986). Peak serum concentrations (tmax) were reachedapproximately 2 hours after oral dosing and the peak serum concentration(Cmax) for PO tramadol was 280±49 ng/mL. The terminal half-life was 5.1hours for PO and 5.2 hours for IV administration. The area under theserum tramadol concentration-time curve (AUC) was 2488±774 ng·h/mL forPO and 3709±977 ng·h/mL for IV administration. Total clearance was467±124 mL/min for PO and 710±174 mL/min for IV administration. Theabsolute bioavailability of the oral dose was 68±13%, based oncomparison of the AUC values, while the estimated absorption of the oraldose was 86-88%. The difference between absorption and bioavailabilitywas attributed to first pass metabolism, which was estimated to be ˜20%.However, the absolute bioavailability approaches 90-100% with continuousdosing, probably due to saturation of first pass metabolism (Liao etal., 1992). Other studies have corroborated these findings (Grond andSablotzki, 2004).

The pharmacokinetic profile of tramadol following i.v. and p.o.administration in humans (n=10, male) is summarized in Table A below(Lintz W, Barth H, Osterloh O, Schmidt-Bothelt E. Bioavailability ofenteral tramadol formulations. 1st communication: capsules. ArzneimForsch Drug Res. 1986; 36:1278-1283). The absolute oral bioavailabilityof tramadol was 68% (±13) in humans.

TABLE A Pharmacokinetics of Tramadol (100 mg) Following Intravenous andOral Administration to Humans Tramadol C_(max) AUC_(0-24 h) CL/F (100mg) (ng/mL) t₁/₂ (h) (ng · h/mL) V_(d) (L) (mL/min) i.v. — 5.2 ± 0.83709 ± 977 203 ± 40 467 ± 124 p.o 280 ± 49 5.1 ± 0.8 2488 ± 774 306 ± 52710 ± 174 Abbreviations: C_(max), maximal concentration; t₁/₂,half-life; AUC, area under the plasma concentration-time curve; CL,clearance; F, bioavailability; V_(d;) volume of distribution

The pharmacokinetic profile of tramadol and the (+)-M1 and (−)-M1metabolites was also evaluated in humans (N=12, male) following p.o.administration of a single 1.5 mg/kg dose of tramadol (Matthiesen, etal., 1993). The data are summarized in Table B below:

TABLE B Pharmacokinetics of Tramadol and the (+) and (−) Enantiomers ofthe M1 Metabolite Tramadol (1.5 CL/F mg/kg, C_(max) T_(max) AUC (mL/min/[100 mg]) (ng/mL) (h) t₁/₂ (h) (ng · h/mL) kg) Tramadol 274 ± 75 1.6 ±0.5 5.9 ± 0.7 2177 ± 722 742 ± 234 (+)-M1 147 ± 39 1.6 ± 0.5 6.0 ± 1.01258 ± 410 642 ± 204 (−)-M1 125 ± 32 1.5 ± 0.5 5.2 ± 0.8  908 ± 298 883± 264 Abbreviations: C_(max), maximal concentration; T_(max), time tomaximal concentration; AUC, area under the plasma concentration-timecurve; CL, clearance; F, bioavailability; t₁/₂, half-life; V_(d); volumeof distribution

Tramadol undergoes hepatic metabolism and both the parent drug and theactive metabolite are excreted by the kidneys. The active metabolite, M1(O desmethyltramadol), is produced by the action of CYP2D6 isozyme ofthe cytochrome P450 enzyme system. It has a half-life of approximately6.7 hours after oral administration (single dose of 100 mg), compared toa half-life of 5.6 hours for tramadol administered intravenously.Hepatic impairment results in decreased metabolism of both the parentcompound and the active metabolite. Tramadol is rapidly distributedafter IV administration with a distribution half-life in the initialphase of 0.31±0.17 hours, followed by a slower distribution phase with ahalf-life of 1.7±0.4 hours (Lintz et al., 1986). The volumes ofdistribution following PO and IV administration were 306 L and 203 L,respectively, indicating that tramadol has a high tissue affinity. Theprotein binding of tramadol is approximately 20%; however, saturation ofbinding sites does not occur in the therapeutic dose range (Ultram®Prescribing Information, 2009).

Elimination half-life increases approximately 2-fold in subjects withrenal or hepatic impairment. Patients who metabolize drugs poorly viaCYP2D6 (Caucasian population prevalence ˜8%) may obtain reduced benefitfrom tramadol due to reduced formation of M1 (Ultram® PrescribingInformation, Ortho-McNeil-Janssen Pharmaceuticals, Inc, 2009).

Studies of IV tramadol in the postoperative setting have shown anacceptable safety profile. Loading doses up to 150 mg IV were notassociated with any serious adverse effects (Silvasti et al., 2000).Also, no serious adverse effects were observed in clinical trials oftramadol with mean (±SD) cumulative doses of 449±66 mg (Rud et al.,1994), 677±473 mg (range 128-1750 mg) (Silvasti et al., 2000), and868.3±412.2 mg (Pang et al., 1999) over 24, 36 and 48 h respectively.

The most common adverse events, nausea, dizziness, headache, somnolence,sweating, fatigue, constipation, dry mouth and vomiting, which areusually mild to moderate in severity and only occasionally lead topremature discontinuation of tramadol.

The Ultram® and Tramal® labels contain several warnings and precautionsregarding use of tramadol. The risk of most of these potential adverseevents can be minimized by decreasing the dose or excluding use oftramadol in subjects with risk factors associated with these known, rareadverse events. Tramadol metabolism is reduced in the setting ofadvanced cirrhosis and renal clearance of both tramadol and itsmetabolites is reduced in individuals with creatinine <30 mL/min. Thus,the dose of tramadol should be reduced by half or the interval doubledin these populations. Dosage adjustment is also recommended inindividuals >75 years of age as they have reduced drug clearance.Tramadol is metabolized by CYP2D6 and CYP3A4; thus, drugs that areinhibitors or inducers of these enzymes can alter tramadol metabolism,resulting in decreased efficacy and/or increased risk of seizures orother adverse effects. Tramadol is associated with a low risk forrespiratory depression, which is increased in the presence of otheropioids, anesthetic agents and other CNS depressants, including alcohol.Respiratory depression due to the opioid activity of tramadol can bereversed with naloxone. Naloxone should be used cautiously as it canpotentiate seizures when administered with tramadol. The full range ofallergic/hypersensitivity reactions have been reported in associationwith tramadol administration, including serious and rarely fatalanaphylactoid reactions.

Potentially life-threatening serotonin syndrome may occur with tramadolproducts with concomitant use of serotonergic drugs such as SSRIs,tricyclic antidepressants, monoamine oxidase inhibitors and triptans.

Tramadol use, particularly with high doses, has been associated withseizures, and the risk of seizures is increased in the presence of drugsthat reduce seizure threshold, head trauma or prior history of seizures.

Human studies evaluating the abuse potential of tramadol, administeredvia IV or PO routes, have also been conducted (Epstein et al., 2006).During the initial dose-ranging studies, seizure was observed followinga tramadol dose of 700 mg IV administered over 1 minute and 300 mg IVdelivered over 2.5 minutes. No seizures were observed with a tramadoldose of 200 mg IV administered over 5 minutes. The authors hypothesizedthat toxicity is likely to limit abuse of high doses of IV tramadol. Ina subsequent study involving 10 experienced opioid abusers, tramadol(100 and 200 mg IV), morphine (10 and 20 mg IV) and placebo wereadministered over 5 minutes. The endpoints in the study were subjective;the extent to which subjects “liked” the effects of the drugs, as wellas their ability to produce effects common to morphine and benzadrine(assessed by the Addiction Research Center Inventory-Morphine BenzadrineGroup [ARCI-MBG] scale). Tramadol and morphine significantly increasedratings of “feel drug effect” compared to placebo. However, neither doseof tramadol increased ratings on the “liking” or ARCI-MBG scale or onany other subjective measure of opiate-like effects. In contrast,morphine 10 and 20 mg doses significantly increased ratings of “liking”and the morphine 20 mg dose increased ratings on the ARCI-MBG scale.Thus, tramadol administered via the parenteral route (IV or IM) isunlikely to be associated with the subjective morphine-like and positivemood effects typical of abuse and addiction.

In accordance with the present invention, it is desirable to provide anintravenous dosing regimen of tramadol which at steady-state provides aplasma concentration with respect to Cmax that is similar or equivalentto the steady-state Cmax provided by a 100 mg oral tramadol dose givenevery 6 hours would be desirable and would be safer and have lesslikelihood of significant side effects than, e.g., the administration of100 mg of tramadol intravenously administered every 6 hours (i.e., samedose and dosing interval as the oral reference standard, Ultram®. It isfurther believed that it would desirable for such an intravenous dosingregimen(s) to provide a steady-state trough plasma level of tramadol(e.g., Cmin) which is at least as high as the steady-state trough levelprovided by a 100 mg oral tramadol dose given every 6 hours. Thesteady-state Cmax of the 100 mg oral dose of tramadol administered every6 hours is about 736 ng/mL. For purposes of the present invention, asimilar or equivalent Cmax provided by an intravenous tramadol dosingregimen would provide a Cmax within the range from about 80% to about125% of the steady-state Cmax of the 100 mg oral tramadol administeredevery 6 hours (e.g., 736 ng/mL; or e.g., from about 588.8 ng/mL to about920 ng/mL). It is especially preferred that the steady-state Cmax of thedosing regimen(s) of the present invention do not exceed theconcentration provided by 100 mg oral tramadol administered every 6hours, at steady-state (e.g., about 701 ng/mL) by more than 15% or morethan about 10%. The co-administration of the acetaminophen in effectiveamounts, e.g, as described herein, is believed to further provide asynergistically improved analgesia than the dose of tramadol alone, andallows for less tramadol to be administered than would otherwise berequired to treat pain in the human patient.

U.S. Pat. No. 9,693,949 (hereby incorporated by reference in itsentirety) describes a method of administering tramadol for treating painin a human patient(s) via an intravenous dosing regimen comprisingintravenously administering a first dose of tramadol to a humanpatient(s) in an amount of about 50 mg; intravenously administering asecond dose of tramadol to the human patient(s) in an amount of about 50mg at about 2 hours after the first dose; intravenously administering athird dose of tramadol to the human patient(s) in an amount of about 50mg at about 2 hours after the second dose; and thereafter intravenouslyadministering additional doses of tramadol to the human patient(s) in anamount of about 50 mg tramadol at dosage intervals of about 4 hours,until the patient no longer requires treatment with tramadol, whereinthe tramadol is tramadol base or a pharmaceutically acceptable salt oftramadol. By virtue of this state-of-the-art dosing regimen, tramadol isintravenously administered seven times on day one of therapy and sixtimes a day thereafter. Thus, as per the above, the '949 patent teachesthe intravenous administration of about 350 mg tramadol on day 1 and 300mg tramadol on day 2 and onward. This is in comparison to the dosingregimen of the present invention, wherein the amount of intravenoustramadol given on a daily basis is about 240 mg. Likewise, with respectto acetaminophen, the dose administered via the present invention on adaily basis will be from about 2600 mg to about 3000 mg versus about4000 mg per day, as currently approved for administration in the U.S. Itis believed that three is no IV tramadol dosage regimen of 60 mgtramadol administered every 6 hours approved or use anywhere in theworld.

In the present invention, the co-administration of acetaminophen at thesame dosage interval as the tramadol (e.g., about every 6 hours), allowsfor the administration of less tramadol while preferably achieving thesame or even better efficacy because of synergistic and non-overlappingmechanisms, despite the reduction in doses of each drug.

A further benefit of the present invention is that the dosing oftramadol and acetaminophen may be simultaneous. If a healthcare providerdesired to administer, e.g., seven doses of tramadol on the first day oftreatment (in accordance with the '949 patent) and four doses ofacetaminophen (e.g., as per the package insert/administration directionsfor Ofirmev, 1000 mg every 6 hours), the healthcare provider would beadministering 11 infusions (each about 15 minutes long) on day one and10 infusions (each about 15 minutes long) on day 2. Instead, as per thepresent invention, the healthcare provider may administer both drugsonly four times a day (about every 6 hours; about 15 minute infusions).

By virtue of the present dosing regimen comprising 60 mg IV tramadolevery 6 hours, the maximum plasma concentration (Cmax) of the tramadolrapidly approaches the maximum concentration found at steady-state withrespect to a dosing regimen of 100 mg tramadol HCl administered orallyevery 6 hours. The Cmax obtained after a number of doses of 60 mg IVtramadol (e.g., after the fourth, fifth, sixth or seventh dose) isapproximately the same as the Cmax at steady-state for a dosing regimenof 100 mg tramadol HCl administered orally every 6 hours. However, incontrast, the oral tramadol dosing regimen takes considerably longer(Cmax₄₄₋₄₈) to reach that maximum tramadol plasma concentration. Asdiscussed in Example 5 of the '949 patent, the Cmax of the 50 mg IVtramadol dosing regimen is about 736 ng/mL±152 and is approached duringthe third dose (see, e.g., Example 5, Table 11 and FIGS. 11-12), whereasthe Cmax of tramadol for the oral 100 mg dosing regimen is about 701ng/ml±178 and occurs at 42-48 hours after the first oral dose isadministered (see, e.g., Example 5, Table 11 and FIGS. 9 and 12).Moreover, in this embodiment the trough levels (plasma concentrations oftramadol) also much more rapidly reach a level similar to the troughlevels at steady-state for the oral 100 mg every 6 hours dosing regimen.It is believed that the fact that (for the 60 mg IV dosing regimen) peakand trough plasma levels similar to steady-state levels found for theoral 100 mg q6h dosing regimen are reached at a such an earlier time maytranslate into improved efficacy (pain relief) for the patients.

It is further believed that the intravenous dosing regimen of theinvention, e.g., as a slow push of a therapeutically effective dose oftramadol contained in a bag over a time period from about 10 to about 20minutes, preferably about 15 minutes, will provide added safety withrespect to the above-mentioned potential adverse events and others, andwill provide lower incidence of side effects associated with tramadoladministration. It is further believed that the intravenous dosingregimen of the invention where a therapeutically effective dose oftramadol is administered to a human patient(s) over a time period fromabout 24 hours to 48 hours in much slower infusion will also providethese benefits.

The intravenous tramadol formulation in accordance with the inventiontypically includes tramadol in the form of its hydrochloride salt.However, one of ordinary skill in the art will appreciate that otherforms of tramadol may be used, including but not limited to allpharmaceutically acceptable salts of tramadol. Such pharmaceuticallyacceptable salts may include, but are not limited to, metal salts suchas sodium salt, potassium salt, secium salt and the like; alkaline earthmetals such as calcium salt, magnesium salt and the like; organic aminesalts such as triethylamine salt, pyridine salt, picoline salt,ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt and the like; inorganic acid saltssuch as hydrochloride, hydrobromide, sulfate, phosphate and the like;organic acid salts such as formate, acetate, trifluoroacetate, maleate,tartrate and the like; sulfonates such as methanesulfonate,benzenesulfonate, p-toluenesulfonate, and the like; amino acid saltssuch as arginate, asparginate, glutamate and the like.

It is contemplated that with respect to the inventive methods for theintravenous administration of tramadol as described herein, otheranalgesics, preferably opioid analgesics, may be used to treatpostoperative pain in the patient(s), as well. It is particularlycontemplated that one or more opioid analgesics will be administeredpost-surgically to the patient as rescue medicine in order to treatbreakthrough pain that the patient may experience.

The term “opioid analgesic” refers to all drugs, natural or synthetic,with morphine-like actions. The synthetic and semi-synthetic opioidanalgesics are derivatives of five chemical classes of compound:phenanthrenes; phenylheptylamines; phenylpiperidines; morphinans; andbenzomorphans, all of which are within the scope of the term. Opioidanalgesics which are useful in the present invention include all opioidagonists or mixed agonist-antagonists, partial agonists, including butnot limited to alfentanil, allylprodine, alphaprodine, anileridine,benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, narceine, nicomorphine,norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propoxyphene,sufentanil, tilidine, mixtures of any of the foregoing, salts of any ofthe foregoing, and the like.

In certain preferred embodiments, opioid analgesics include morphine,oxycodone, codeine, dihydrocodeine, diacetylmorphine, hydrocodone,hydromorphone, levorphanol, oxymorphone, alfentanil, buprenorphine,butorphanol, fentanyl, sufentanyl, meperidine, methadone, nalbuphine,propoxyphene and pentazocine or pharmaceutically acceptable saltsthereof. In certain preferred embodiments, the opioid agonist ismorphine. Equianalgesic doses of these opioids are generally known tothose persons having ordinary skill in the art.

In certain embodiments, the patient's need for additional analgesictreatment beyond the intravenous tramadol may be ascertained via the useof a surrogate measure of pain. Pain rating scales are used in dailyclinical practice to measure pain intensity. The commonly usedmeasurement scales include the Visual Analog Scale (VAS), the GraphicRating Scale (GRS), the Simple Descriptor Scale (SDS), the NumericalRating Scale (NRS), and the Faces Rating Scale (FRS). All of thesescales have been documented as being valid measures of pain intensity.The three scales most commonly used in the U.S. are the numerical, wordand faces scales. One preferred pain rating scale is the visual analogscale (VAS), a 10 cm. vertical or horizontal line with word anchors atthe extremes, such as “no pain” on one end and “pain as bad as it couldbe” at the other. The patient is asked to make a mark along the line torepresent pain intensity.

Alternatively, the graphic rating scale (GRS) is a variation of thevisual scale which adds words or numbers between the extremes. Wordingadded might include “no pain”, “mild”, “severe”. The descriptor scale(SDS) is a list of adjectives describing different levels of painintensity. For example pain intensity may be described as “no pain”,“mild”, “moderate” or “severe”. The numerical pain rating scale (NPRS)refers to a numerical rating of 0 to 10 or 0 to 5 or to a visual scalewith both words and numbers. The patient is asked to rate the pain with0 being no pain and 10 being the worst possible pain. The faces scalewas developed for use with children. This scale exists in severalvariations but relies on a series of facial expressions to convey painintensity. Grouping patients' rating of pain intensity as measured witha numerical scale ranging from 0 to 10 into categories of mild,moderate, and severe pain is useful for informing treatment decisions,and interpreting study outcomes. In 1995, Serlin and colleagues (Pain,1995, 277-84) developed a technique to establish the cut points formild, moderate, and severe pain by grading pain intensity and functionalinference. Since then, a number of studies have been conducted tocorrelate the numerical scales, for example the NPRS, with cutpointsrelated to levels of pain intensity. Common severity cutpoints are (1 to4) for mild pain, (5 to 6) for moderate pain, and (7 to 10) for severepain.

Surrogate measures of opioid efficacy (analgesia) include sedation,respiratory rate and/or pupil size (via pupillometry), and visualanalogue scale (“VAS”) for “drug effect”. The Sum of Pain IntensityDifferences (SPID) through 48 hours post first dose (SPID48) at rest maybe used as a primary measure of efficacy.

The intravenous tramadol/acetaminophen dosing regimens of the inventionmay be used in the in the hospital or day hospital setting and thereforeadministered by medical staff. The tramadol hydrochloride injection forintravenous use and its dosing regimen can fill an important need inaddition to tramadol (e.g., ULTRAM®) tablets and tramadol (e.g., ULTRAM®ER) extended-release tablets by providing this safe and effectiveinjectable analgesic with a novel mechanism of action (μ-opioid agonistand monoaminergic reuptake inhibition) for use in the acutepost-operative setting. These dosing regimens may be used, e.g., for alltypes of surgery, including orthopedic surgery (e.g., total kneereplacement, bunionectomy) or soft tissue surgery (e.g., electiveabdominoplasty).

CONCLUSION

All patents and publications identified in the above paragraphs arehereby incorporated by reference in their entireties. It will be readilyapparent to one of ordinary skill in the relevant arts that othersuitable modifications and adaptations to the methods and applicationsdescribed herein are suitable and may be made without departing from thescope of the invention or any embodiment thereof. While the inventionhas been described in connection with certain embodiments, it is notintended to limit the invention to the particular forms set forth, buton the contrary, it is intended to cover such alternatives,modifications and equivalents as may be included within the spirit andscope of the invention as defined by the following claims. All of thepatents and publications cited herein are hereby incorporated byreference.

What is claimed is:
 1. A method of administering tramadol for treating pain via an intravenous dosing regimen, comprising intravenously administering a first dose of tramadol to a human patient in an amount from about 45 mg to about 80 mg; and concurrently administering an intravenous dose of acetaminophen in an amount from about 500 mg to about 1000 mg; and thereafter intravenously administering the doses of tramadol and acetaminophen about every 6 hours until the patient no longer requires treatment with intravenous tramadol, wherein the tramadol is tramadol base or a pharmaceutically acceptable salt of tramadol.
 2. The method of claim 1, wherein the intravenous dosing regimen provides a Cmax of tramadol which is similar to the Cmax of an oral dose of 100 mg tramadol HCl given every 6 hours at steady-state.
 3. The method of claim 1, wherein each dose of tramadol is about 60 mg tramadol hydrochloride, and each dose of acetaminophen is from about 650 mg to about 750 mg.
 4. The method of claim 1, wherein each dose of tramadol is about 60 mg.
 5. The method of claim 4, the intravenous dosing regimen of the invention provide a Cmax of tramadol at steady-state that is from about 80% to about 125% of the Cmax provided at steady-state by a 100 mg oral dose of tramadol HCl given every 6 hours.
 6. The method of claim 4, wherein the intravenous dosing regimen provides a Cmax of tramadol at steady-state from about 80% to about 125% of about 736 ng/mL.
 7. The method of claim 1, further comprising continuing to administer additional doses of tramadol and acetaminophen to the human patient for at least about 42 hours after the first administered dose of tramadol.
 8. The method of claim 1, further comprising diluting the dose of tramadol and acetaminophen in from about 50 ml to about 500 ml of a pharmaceutically acceptable fluid for injection, and standardizing the administration of the injection of the dose of tramadol and acetaminophen via the use of a pump.
 9. The method of claim 8, wherein the dose is provided in the form of a sterile solution at a concentration of about 60 mg tramadol hydrochloride and from about 650 mg to about 750 acetaminophen contained in one or more ampoules.
 10. The method of claim 9, wherein the ampoules contain the dose of tramadol together acetaminophen with a buffering agent in water for injection.
 11. The method of claim 1, further comprising diluting the dose of tramadol and acetaminophen into an IV bag for administration to the human patient.
 12. The method of claim 1 wherein the patient is undergoing surgery, further comprising administering a first dose of tramadol/acetaminophen to the patient intra-operatively at wound closure, or from first demand of analgesia postoperatively, and administering further doses of intravenous tramadol/acetaminophen for at least two days post-surgery.
 13. The method of claim 1, wherein the human patient is suffering from acute post-operative pain.
 14. The method of claim 13, further comprising switching the human patient after at least three intravenous doses of tramadol/acetaminophen, to oral doses of the same amount of tramadol and acetaminophen previously administered intravenously, such that the Cmax of tramadol at the time the human patient is switched to oral doses is similar to the Cmax provided at steady-state by a dosing regimen of 100 mg tramadol HCl administered orally every 6 hours.
 15. The method of claim 1, further comprising administering an opioid analgesic which is not tramadol to the human patient to treat breakthrough pain.
 16. A method of administering tramadol for treating pain via an intravenous dosing regimen, comprising intravenously administering a first dose of tramadol to a human patient in an amount of about 60 mg; and concurrently administering an intravenous dose of acetaminophen in an amount of about 650 mg; and thereafter intravenously administering the doses of tramadol and acetaminophen about every 6 hours until the patient no longer requires treatment with intravenous tramadol, wherein the tramadol is tramadol base or a pharmaceutically acceptable salt of tramadol, such that the intravenous dosing regimen provides a Cmax of tramadol which is similar to the Cmax of an oral dose of 100 mg tramadol HCl given every 6 hours at steady-state.
 17. The method of claim 16, the intravenous dosing regimen of the invention provide a Cmax of tramadol at steady-state that is from about 80% to about 125% of the Cmax provided at steady-state by a 100 mg oral dose of tramadol HCl given every 6 hours.
 18. The method of claim 17, wherein the intravenous dosing regimen provides a Cmax of tramadol at steady-state from about 80% to about 125% of about 736 ng/mL. 